Methods of stabilizing molecular weight of polymer stents after sterilization

ABSTRACT

Methods of stabilizing the molecular weight of polymer stents scaffolds after E-beam sterilization are disclosed. The molecular weight of the polymer of the irradiated scaffolds is stabilized through exposure to gas containing oxygen.

This application is a continuation application of U.S. application Ser.No. 13/103,890 and is incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to methods of manufacturing polymeric medicaldevices, in particular, stents.

2. Description of the State of the Art

This invention relates to radially expandable endoprostheses, that areadapted to be implanted in a bodily lumen. An “endoprosthesis”corresponds to an artificial device that is placed inside the body. A“lumen” refers to a cavity of a tubular organ such as a blood vessel. Astent is an example of such an endoprosthesis. Stents are generallycylindrically shaped devices that function to hold open and sometimesexpand a segment of a blood vessel or other anatomical lumen such asurinary tracts and bile ducts. Stents are often used in the treatment ofatherosclerotic stenosis in blood vessels. “Stenosis” refers to anarrowing or constriction of a bodily passage or orifice. In suchtreatments, stents reinforce body vessels and prevent restenosisfollowing angioplasty in the vascular system. “Restenosis” refers to thereoccurrence of stenosis in a blood vessel or heart valve after it hasbeen treated (as by balloon angioplasty, stenting, or valvuloplasty)with apparent success.

Stents are typically composed of scaffolding that includes a pattern ornetwork of interconnecting structural elements or struts, formed fromwires, tubes, or sheets of material rolled into a cylindrical shape.This scaffolding gets its name because it physically holds open and, ifdesired, expands the wall of the passageway. Typically, stents arecapable of being compressed or crimped onto a catheter so that they canbe delivered to and deployed at a treatment site.

Delivery includes inserting the stent through small lumens using acatheter and transporting it to the treatment site. Deployment includesexpanding the stent to a larger diameter once it is at the desiredlocation. Mechanical intervention with stents has reduced the rate ofrestenosis as compared to balloon angioplasty. Yet, restenosis remains asignificant problem. When restenosis does occur in the stented segment,its treatment can be challenging, as clinical options are more limitedthan for those lesions that were treated solely with a balloon.

Stents are used not only for mechanical intervention but also asvehicles for providing biological therapy. Biological therapy usesmedicated stents to locally administer a therapeutic substance.Effective concentrations at the treated site require systemic drugadministration which often produces adverse or even toxic side effects.Local delivery is a preferred treatment method because it administerssmaller total medication levels than systemic methods, but concentratesthe drug at a specific site. Local delivery thus produces fewer sideeffects and achieves better results.

A medicated stent may be fabricated by coating the surface of either ametallic or polymeric scaffolding with a polymeric carrier that includesan active or bioactive agent or drug. Polymeric scaffolding may alsoserve as a carrier of an active agent or drug.

The stent must be able to satisfy a number of mechanical requirements.The stent must be capable of withstanding the structural loads, namelyradial compressive forces, imposed on the stent as it supports the wallsof a vessel. Therefore, a stent must possess adequate radial strength.Radial strength, which is the ability of a stent to resist radialcompressive forces, relates to a stent's radial yield strength andradial stiffness around a circumferential direction of the stent. Astent's “radial yield strength” or “radial strength” (for purposes ofthis application) may be understood as the compressive loading, which ifexceeded, creates a yield stress condition resulting in the stentdiameter not returning to its unloaded diameter, i.e., there isirrecoverable deformation of the stent. When the radial yield strengthis exceeded the stent is expected to yield more severely and only aminimal force is required to cause major deformation.

Once expanded, the stent must adequately maintain its size and shapethroughout its service life despite the various forces that may come tobear on it, including the cyclic loading induced by the beating heart.For example, a radially directed force may tend to cause a stent torecoil inward. In addition, the stent must possess sufficientflexibility to allow for crimping, expansion, and cyclic loading.

Some treatments with stents require its presence for only a limitedperiod of time. Once treatment is complete, which may include structuraltissue support and/or drug delivery, it may be desirable for the stentto be removed or disappear from the treatment location. One way ofhaving a stent disappear may be by fabricating a stent in whole or inpart from materials that erodes or disintegrate through exposure toconditions within the body. Stents fabricated from biodegradable,bioabsorbable, and/or bioerodable materials such as bioabsorbablepolymers can be designed to completely erode only after the clinicalneed for them has ended.

However, there are several challenges making a bioabsorbable polymericstent. These include making a stent with sufficient radial strength,stiffness, and toughness or resistance to fracture. Another challenge ismaintaining the properties of the finished stent from the end ofmanufacturing to the time of implantation. Medical devices are typicallystored for an indefinite or variable period of time after fabrication.Since storage time will vary for each device that is made, the problemof product consistency arises if properties change over time.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference, and as if eachsaid individual publication or patent application was fully set forth,including any figures, herein.

SUMMARY OF THE INVENTION

Various embodiments of the present invention include a method of makinga stent, comprising: providing a polymeric stent scaffolding disposed ona catheter; exposing the scaffolding to E-beam radiation forsterilization, wherein the scaffolding is exposed to a gas containingoxygen during the exposure, wherein an oxygen content of the gas isgreater than 1%; and packaging the scaffolding in an inert gasenvironment.

Further embodiments of the present invention include a method of makinga stent, comprising: providing a polymeric stent scaffolding disposed ona catheter, wherein the scaffolding is sealed in a package permeable toand comprising air; and exposing the packaged scaffolding to E-beamradiation for sterilization; after the radiation exposure, disposingpackage in a gas impermeable package, wherein oxygen in the air quenchesfree radicals generated by the radiation exposure; removing the air fromthe packages; and filling the packages with an inert gas and sealing thepackages.

Additional embodiments of the present invention include a method ofmaking a stent, comprising: providing a polymeric stent scaffolding;exposing the scaffolding to E-beam radiation for sterilization, whereinthe scaffolding is exposed to an inert gas environment duringsterilization; exposing the irradiated scaffolding to air to quench freeradicals generated by the radiation exposure and stabilize a molecularweight of the scaffolding polymer; and after the period of time, storingscaffolding in an inert gas environment.

Other embodiments of the present invention include a method of making astent, comprising: providing a package having an inner gas permeablelayer and an outer gas impermeable layer, wherein the inner layer andthe outer layer have an inert gas environment within and the inner layerand outer layer are sealed, wherein a polymer scaffolding is disposedwithin the inner layer; exposing the scaffolding to E-beam radiation forsterilization; allowing fluid communication between ambient air and theouter layer to expose the scaffolding to air for a period of time; afterthe period of time, removing air from and sealing the gas impermeablepackage; and storing the scaffolding in an inert gas environment.

Further embodiments of the present invention include a method of makinga stent, comprising: providing a polymeric stent scaffolding; exposingthe scaffolding to E-beam radiation for sterilization, wherein duringthe exposure the scaffolding is in a sealed gas impermeable packagecontaining a gas mixture of oxygen and an inert gas, wherein the oxygencontent of the gas mixture is 1% or less; and storing the scaffolding inthe gas mixture until use of the scaffolding, wherein the oxygen in thegas mixture quenches free radicals in the scaffolding polymer andstabilizes the molecular weight of the scaffolding polymer.

Additional embodiments of the present invention include a method ofmaking a stent, comprising: providing a polymeric stent scaffolding;selecting a final Mn of the polymer of the scaffolding; irradiating thescaffolding with E-beam radiation for sterilization in an inert gasenvironment, wherein the polymer of the scaffolding has an initial Mnafter the irradiation; allowing the Mn of the irradiated scaffolding toincrease from the initial Mn to the final Mn in the inert gasenvironment; exposing the scaffolding to an oxygen-containing gas tostabilize the Mn of the scaffolding at the final Mn; and storing thestabilized scaffolding in an inert gas environment.

Further embodiments of the present invention include a method of makinga stent, comprising: providing a package having a first side that isimpermeable and a second side that is gas permeable, wherein the firstside has an inert gas environment within and the second side has ambientair, wherein a polymeric scaffolding is disposed within the first side,where the sides are connected by a movable sealer that allows movementof the scaffolding from the first side to the second side without fluidcommunication between the sides; exposing the scaffolding to E-beamradiation for sterilization; after a period of time after sterilization,shifting the scaffolding with the movable sealer to the second side toexpose the stent to air; and after a selected stabilization time,shifting the scaffolding to the first side to the inert gas environment;and resealing the first side with inert gas.

Additional embodiments of the present invention include a method ofmaking a stent, comprising: providing a package having a first side anda second side that are both gas impermeable, wherein the first side hasan inert gas environment and the second side has a mixture of an inertgas and oxygen, wherein a polymeric scaffolding is disposed within thefirst side, wherein the sides are connected by a valve that allows fluidcommunication between the first side to the second side when the valveis open; exposing the scaffolding to E-beam radiation for sterilization;after a period of time after sterilization, opening the valve to allowfluid communication between the first side and the second side to exposethe scaffolding to oxygen and terminate free radicals in thescaffolding; and after a selected stabilization time, closing the valveand replacing the inert gas and mixture in the first side with an inertgas environment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a stent.

FIG. 2 depicts a normalized free radical decay profile of PLLAscaffolding samples stored under different environments (argon vs.oxygen) after E-beam sterilization in argon.

FIG. 3 depicts the Mn versus time of a PLLA scaffolding after radiationsterilization aged in argon.

FIG. 4 depicts a normalized free radical decay of E-beam irradiated PLLAscaffolding samples sterilized and aged in a sealed foil pouch in argonand samples sterilized and aged in a Tyvek® pouch.

FIG. 5A depicts a schematic representation of a Tyvek® pouch with astent contained within.

FIG. 5B depicts the Tyvek® pouch of FIG. 5B disposed within an aluminumpouch.

FIG. 6 depicts a schematic representation of a double-layered pouch.

FIG. 7 depicts the free radical decay in irradiated PLLA scaffoldingsamples sterilized and stored in containers with different oxygenconcentrations, 0%, 0.002%, and 1%.

FIG. 8 depicts the Mn versus time of a PLLA scaffolding that is notirradiated with E-beam radiation.

FIG. 9 depicts the Mn versus time for irradiated PLLA scaffoldingsamples under different packaging environments.

FIG. 10 depicts a schematic representation of a two-sided pouch havingan aluminum side and a Tyvek® side, which has air within.

FIG. 11 depicts a schematic representation of a pouch with a firstaluminum side and a second aluminum side.

DETAILED DESCRIPTION OF THE INVENTION

Various embodiments of the present invention relate to manufacture ofpolymeric implantable medical devices. In particular, the embodimentsinclude methods of stabilizing the properties of polymer stents afterradiation sterilization.

The methods described herein are generally applicable to any amorphousor semi-crystalline polymeric implantable medical device, especiallythose that have load bearing portions when in use or have portions thatundergo deformation during use. In particular, the methods can beapplied to tubular implantable medical devices such as self-expandablestents, balloon-expandable stents, and stent-grafts.

A stent may include a pattern or network of interconnecting structuralelements or struts. FIG. 1 depicts a view of a stent 100. In someembodiments, a stent may include a body, backbone, or scaffolding havinga pattern or network of interconnecting structural elements 105. Stent100 may be formed from a tube (not shown). The structural pattern of thedevice can be of virtually any design. The embodiments disclosed hereinare not limited to stents or to the stent pattern illustrated in FIG. 1.The embodiments are easily applicable to other patterns and otherdevices. The variations in the structure of patterns are virtuallyunlimited.

A stent such as stent 100 may be fabricated from a polymeric tube or asheet by rolling and bonding the sheet to form the tube. A tube or sheetcan be formed by extrusion or injection molding. A stent pattern, suchas the one pictured in FIG. 1, can be formed in a tube or sheet with atechnique such as laser cutting or chemical etching. The stent can thenbe crimped on to a balloon or catheter for delivery into a bodily lumen.

An implantable medical device of the present invention can be madepartially or completely from a biodegradable, bioresorbable,bioabsorbable, or biostable polymer. A polymer for use in fabricating animplantable medical device can be biostable, bioresorbable,bioabsorbable, biodegradable or bioerodable. Biostable refers topolymers that are not biodegradable. The terms biodegradable,bioresorbable, bioabsorbable, and bioerodable are used interchangeablyand refer to polymers that are capable of being completely degradedand/or eroded into different degrees of molecular levels when exposed tobodily fluids such as blood and can be gradually resorbed, absorbed,and/or eliminated by the body. The processes of breaking down andabsorption of the polymer can be caused by, for example, hydrolysis andmetabolic processes.

A stent made from a biodegradable polymer is intended to remain in thebody for a duration of time until its intended function of, for example,maintaining vascular patency and/or drug delivery is accomplished. Afterthe process of degradation, erosion, absorption, and/or resorption hasbeen completed, no portion of the biodegradable stent, or abiodegradable portion of the stent will remain. In some embodiments,very negligible traces or residue may be left behind.

The duration of a treatment period depends on the bodily disorder thatis being treated. In treatments of coronary heart disease involving useof stents in diseased vessels, the duration can be in a range fromseveral months to a few years. The duration is typically up to about sixmonths, twelve months, eighteen months, or two years. In somesituations, the treatment period can extend beyond two years.

As indicated above, a stent has certain mechanical requirements such ashigh radial strength, high stiffness or high modulus, and high fracturetoughness. A stent that meets such requirements greatly facilitates thedelivery, deployment, and treatment of a diseased vessel. With respectto radial strength and stiffness, a stent must have sufficient radialstrength to withstand structural loads, namely radial compressiveforces, imposed on the stent so that the stent can supports the walls ofa vessel at a selected diameter for a desired time period. A polymericstent with inadequate radial strength and/or stiffness can result in aninability to maintain a lumen at a desired diameter for a sufficientperiod of time after implantation into a vessel.

In addition, the stent must possess sufficient toughness or resistanceto fracture to allow for crimping, expansion, and cyclic loading. Theseaspects of the use of the stent involve deformation of various portionsof the stent. Sufficient toughness is important to prevent cracking orfracture during use which could lead to premature mechanical failure ofthe stent.

The strength to weight ratio of polymers is usually smaller than that ofmetals. To compensate for this, a polymeric stent can requiresignificantly thicker struts than a metallic stent, which results in anundesirably large profile. The strength deficiency of polymers isaddressed in the present invention by incorporating a deformation stepin the stent fabrication process by subjecting the polymer construct todeformation. Deforming polymers tends to increase the strength along thedirection of deformation, which is believed to be due to the inducedpolymer chain orientation along the direction of deformation. Forexample, radial expansion of a polymeric tube construct providespreferred circumferential polymer chain orientation in the tube.Additionally, stretching a tube provides preferred axial orientation ofpolymer chains in the tube. Thus, a stent fabrication process caninclude radially deforming a polymer tube and cutting a stent from thedeformed tube. The deformation process also results in strain inducedcrystallization, increasing the crystallinity of the construct whichincreases the strength of the polymer.

Semi-crystalline polymers that are stiff or rigid under biologicalconditions or conditions within a human body are particularly suitablefor use as a scaffolding material. Specifically, polymers that have aglass transition temperature (Tg) sufficiently above human bodytemperature which is approximately 37° C., should be rigid uponimplantation. Poly(L-lactide) (PLLA) is an example of such a polymer.These polymers, however, may exhibit a brittle fracture mechanism inwhich there is little or no plastic deformation prior to failure. As aresult, it is important not only to improve the strength of suchpolymers when making a device, but also to improve the fracturetoughness for the range of use of a stent, specifically for the rangedeformation during use of the stent. In particular, it is important fora stent to have high resistance to fracture throughout the range of useof a stent, i.e., crimping, delivery, deployment, and during a desiredtreatment period after deployment.

Exemplary biodegradable polymers for use with a bioabsorbable polymerscaffolding include poly(L-lactide) (PLLA), poly(D-lactide) (PDLA),polyglycolide (PGA), and poly(L-lactide-co-glycolide) (PLGA). Withrespect to PLGA, the stent scaffolding can be made from PLGA with a mole% of GA between 5-15 mol %. The PLGA can have a mole % of (LA:GA) of85:15 (or a range of 82:18 to 88:12), 95:5 (or a range of 93:7 to 97:3),or commercially available PLGA products identified being 85:15 or 95:5PLGA.

The fabrication methods of a bioabsorbable stent for use in the methodsof treatment described herein can include the following steps:

(1) forming a polymeric tube using extrusion,

(2) radially deforming the formed tube,

(3) forming a stent scaffolding from the deformed tube by lasermachining a stent pattern in the deformed tube with laser cutting,

(4) optionally forming a therapeutic coating over the scaffolding,

(5) crimping the stent over a delivery balloon, and

(6) sterilization with election-beam (E-beam) radiation.

In step (2) above, the extruded tube may be radially deformed toincrease the radial strength of the tube, and thus, the finished stent.The increase in strength reduces the thickness of the struts required tosupport a lumen with the stent when expanded at an implant site. Inexemplary embodiments, the strut thickness can be 100-200 microns, ormore narrowly, 120-180, 130-170, or 140-160 microns.

Detailed discussion of the manufacturing process of a bioabsorbablestent can be found elsewhere, e.g., U.S. Patent Publication No.20070283552, which is incorporated by reference herein.

A packaged stent and catheter are sterilized to reduce the bioburden ofthe stent and delivery system to a specified level. Bioburden refersgenerally to the number of microorganisms with which an object iscontaminated. The degree of sterilization is typically measured by asterility assurance level (SAL) which refers to the probability of aviable microorganism being present on a product unit aftersterilization. The required SAL for a product is dependent on theintended use of the product. For example, a product, such as a stent, tobe used in the body's fluid path is considered a Class III device andrequires an SAL of 10⁻⁶. SAL's for various medical devices can be foundin materials from the Association for the Advancement of MedicalInstrumentation (AAMI) in Arlington, Va.

A stent is typically sterilized after mounting the stent at the end of acatheter by crimping. Prior to sterilization, the stent-catheterassembly is placed in a package and sealed. The package is typicallymade of a gas-impermeable material such as aluminum foil. The packageremains sealed after sterilization until the time of implantation. Theinterior of the packaging is typically an inert gas such as argon.

An inert gas refers generally to a non-reactive gas. Inert gases includenoble gases such as argon and helium. Inert gases also include compoundgases that are non-reactive due to the valence, the outermost electronshell, being complete, such as diatomic nitrogen. The inert gasenvironment or atmosphere may have 0% oxygen or may contain a smallamount of oxygen, for example, less than 0.01%, 0.005%, 0.002, or lessthan 0.001% oxygen. The content of gases is expressed in mole percent,unless otherwise specified.

The packaging of the stent in an inert gas may be achieved by vacuumevacuation of the packaging followed by a backfill of the packaging withan inert gas such as argon. The evacuation and backfill process can berepeated to assure complete removal of oxygen. The final oxygen contentof the packaging atmosphere may be approximately 0.002% or less, 0.002%to 0.01%, 0.01% to 0.015%, 0.015% to 0.02%, or 0.02% to 0.04%.

The packaging is designed to prevent exposure of the stent to anybioburden such as bacteria as well as non-inert gases such as oxygen aswell as moisture. Oxygen and moisture may adversely affect theproperties of a drug delivery coating, and thus, the drug deliveryprofile. Additionally, moisture can also cause degradation of thescaffolding. Unless otherwise specified, “oxygen” refers to diatomicoxygen. Irradiation can convert diatomic oxygen to ozone, which canquench free radicals.

The sterilization can be performed by exposing the stent and catheter toradiation, for example, electron beam (E-beam), gamma ray, and x-raysterilization. A sterilization dose can be determined by selecting adose that provides a required SAL. A sample can be exposed to therequired dose in one or multiple passes. An exemplary radiation dose forsterilization of a stent may be 20-50 kGy or any value between, forexample, 25 kGy.

During E-beam irradiation of a bioabsorbable scaffolding, such as a PLLAscaffolding, energy is deposited uniformly across the device. Theirradiation leads to polymer chain scission, excitation of themacromolecules, and the formation of free radicals. Free radicals referto atomic or molecular species with unpaired electrons on an otherwiseopen shell configuration. Free radicals can be formed by oxidationreactions. These unpaired electrons are usually highly reactive, so freeradicals are likely to take part in chemical reactions, including chainreactions. These free radicals generated proceed to react with eachother or initiate further reactions within the polymer chains. Theoutcomes of these reactions will be recombination, branching,crosslinking, chain scission, or propagation.

The immediate effect of the irradiation arises from chain scission sincea decrease in molecular weight is observed after exposure to theradiation. For example, a PLLA stent scaffolding with a number averagemolecular weight (Mn)=260 kDa before E-beam sterilization decreases toan Mn between 70-80 kDa immediately after a radiation dose of 27.5 kGy.The immediate decrease in the molecular weight is not generally aproblem, as long at the molecular weight after sterilization is at adesired level. A desired post-sterilization molecular weight may beobtained by adjusting the molecular weight resin. The Mn of a PLLAscaffolding post-sterilization may be 60 to 65 kDa, 65-70 kDa, 70 to 80kDa, or 80 to 90 kDa.

Thus, it was known to the inventors that radiation sterilization of abioabsorbable stent scaffolding causes a drop in molecular weightimmediately after exposure. It was also known that radiationsterilization causes the generation of free radicals in the polymer.However, decay mechanism of the free radicals in the polymer scaffoldingwas not. Nor was the impact of the free radicals or radiationsterilization in general on stent properties, beyond the immediatechanges, over a longer term (e.g., hours, days, weeks, months afterirradiation.

Given the potential of free radicals to alter the long term propertiesof a bioabsorbable polymer scaffolding, it is important to accuratelydetect free radical type, level, and especially its change with timeafter sterilization. This offers very valuable information for designand modification of a bioabsorbable polymer scaffolding.

Electron spin resonance spectroscopy (ESR) technique has been used forthe detection of free radicals. The original implementation of thismethod originally used by the inventors was used commonly in variousindustrial applications. According to that original method, a stent issterilized in an inert gas environment in a pouch, the stent is takenout of the pouch, and stored in a glass container. Then the informationabout free radical level, type and its change with time is detected andestimated based on measurement of the spins of unpaired electrons in amagnetic field. All the previous ESR results based on this originalmethod showed that the half-life of the generated free radicals is veryshort, and therefore, based on these results would not be expected tocause any significant impact on final stent product properties.

The inventors then considered a hypothesis that sample storage gasenvironment might have a potential impact on free radical decay. Whilethe stent scaffolding is stored in an argon sealed pouch prior toimplantation, the test samples in the original ESR method were stored ina regular glass container filled with air.

The inventors considered whether ESR measurement methods that wouldmimic the storage environment would show a free radical decay profiledifferent from the original method. In one alternative method, the ESRmeasurements may be performed on a sample in a specially designedcontainer filled with an inert gas such as argon. Such a method maymimic the real packaging environment in the pouch.

Another alternative method was applied to generating a free radicaldecay profile of irradiated PLLA scaffolding. In this method, a set ofirradiated samples were stored in separate sealed gas impermeablealuminum pouches. The samples were taken out of a pouch at differenttimes. After a sample was taken out of pouch, it would immediately beplaced in the ESR equipment for free radical detection. By running ESRusing samples stored in the argon sealed pouch at different times andcollecting all received data together, a free radical decay profile wasobtained.

Free radical decay profiles for PLLA scaffoldings sterilized in an inertargon atmosphere were generated according to the alternative methoddescribed above. The results surprisingly show the presence ofmoderately persistent free radicals. FIG. 2 depicts a normalized freeradical decay profile of E-beam irradiated PLLA scaffolding using thealternative method of samples aged in a sealed pouch with argon. FIG. 2also shows free radical decay profile of samples aged in air. Theresults from the alternative method in FIG. 2 clearly show that the freeradicals exist in the scaffolding more than 3 weeks after electron beamprocessing of the scaffolds while in the samples exposed to air, thefree radicals decay to near zero in about 1 day.

During the relatively long period of free radical decay in the former,it is believed that the free radicals are related to temporal changes inmolecular weight, thereby increasing variability of the product.Measurements according to the original method show that a decay to zeroin about 1 day, and thus is not a reflection of the decay of a PLLAscaffolding in an inert gas environment.

These results showed that the long term free radical decay might causecontinued molecular weight change of scaffolding after E-beamsterilization. The inventors have found surprisingly the molecularweight of a PLLA scaffolding continues to increase up to about 40 daysafter E-beam sterilization. FIG. 3 depicts the Mn versus time of a PLLAscaffolding after radiation sterilization with a dose of 27.5 kGy andaged in argon. As indicated above, the Mn is shown to increase from aninitial value after radiation exposure to about 110 kDa 40 days afterexposure. The decay profile of the free radicals suggests the molecularweight change may be associated with free radicals generated fromsterilization.

The significance of the time scale of such changes is the impact onproduct consistency. It is desired generally for the properties of amedical device to be independent of the storage time. More importantly,it is desirable for the performance of the device to be independent ofstorage time. Changes in some properties may not significantly affectthe performance of the device, while other changes may.

The consistency of molecular weight at implantation is important sincethe inventors have recognized that the initial molecular weight,specifically Mn, is a major component in determining the degradationprofile of the scaffolding. In order to heal a diseased vessel, ascaffolding must have a proper degradation profile. The scaffoldingshould maintain radial strength for a period of time to allow healing ofthe vessel. After this period, the scaffolding radial strength maydecrease and the stent should absorb away as quickly and safely aspossible. The inventors have found that molecular weight is one ofseveral variables that impact total resorption time. Increasing theconsistency of molecular weight will therefore reduce variability in thetotal resorption time.

One way to address the product stability and consistency issue, orequivalently, addressing the control of the post-sterilization molecularweight change, is to condition a sterilized final product for a periodof time after sterilization prior to release. For example, the productmay be conditioned 3 weeks at room temperature or 7-10 days at anelevated temperature such as 30° C. This conditioning would stabilizethe Mn or level off Mn change before release of the product. In thiscase, the properties of the released product would be stable, but theconditioning would result only in a molecular weight at the final highend.

Various embodiments of the present invention include methods ofstabilizing the properties of a polymeric stent scaffolding and coatingand preventing changes in properties as a function of time caused byradiation sterilization. The methods include exposing the scaffolding tooxygen during, after, or both during and after radiation sterilizationto stabilize molecular weight and other properties. The exposure may beand is desirable performed in a manner that preserves the degree ofsterility of the stent or reduction in bioburden of the stent providedby the radiation sterilization. The sterility can be maintained byallowing the oxygen exposure through a gas permeable material or packagethat allows gas permeation while prevent permeation of bioburden.Exposure to oxygen or oxygen-containing gas according to the presentinvention does not refer to exposure to a gas with a residual oxygencontent, for example, in evacuated and inert gas backfilled containerstypically used for post-sterilization storage which can be about 0.002%or less oxygen content.

Exposing sterilized stents to oxygen is contrary the generally acceptedpractice in the art which focuses on isolating pre- and post-sterilizedstent from non-inert environment, e.g., reactive gases and moisture.Specifically, it is believed that exposing stents to atmospheric levelsof oxygen causes may cause an additional drop in the molecular weight ofPLLA. As used herein, “oxygen” refers to diatomic oxygen, O₂.Stabilizing the molecular weight may refer to less than a 10% change inMn over a period after radiation exposure of at least 30 days, 30 to 60days, or greater than 60 days.

The inventors have found from several studies that exposing the stentscaffolding to an oxygen-containing gas such as air during or afterradiation exposure reduces or prevents further changes in molecularweight and other properties with time. It is believed from these studiesthat oxygen reacts with the free radicals which renders the freeradicals non-reactive or terminates the free radicals. Therefore, thefree radicals react with and are terminated by the oxygen rather thanreacting with the polymer chains of the stent polymer. The terminationor quenching of the free radicals occurs over a much shorter time framethan the decay of the free radicals in an inert environment.

In certain embodiments of the present invention, a method of making astent includes providing a stent-catheter assembly including a polymericstent scaffolding disposed on a catheter. The scaffolding is exposed toradiation, such as E-beam radiation, to sterilize. The scaffolding isexposed to an oxygen-containing gas during the radiation sterilization.For example, the stent-catheter assembly is exposed to air. Theoxygen-containing gas may be sufficient to quench or terminate all orall but a residual amount (e.g., less than 5×10⁷ DI/mg) of the freeradicals in a short period of time, for example, in less than 1 hr, 5hrs, 12 hrs, 1 day, 2 days, or less than 5 days. The exposure tooxygen-containing gas can continue for a period of time after theradiation exposure, for example, until the free radicals are terminated,equivalently, the free radicals have decayed to zero or below a level atwhich the molecular weight of the scaffolding polymer is stabilized fora long term, such as 2 weeks, 1 month, or longer than 1 month. The stentmay then be stored in an inert gas atmosphere indefinitely, for example,until implantation. An exemplary molecular weight profile according tothese embodiments is illustrated by study D in Table 1 and FIG. 9.

FIG. 4 depicts the free radical decay profiles of irradiated PLLAscaffolding for two cases, (1) sterilized in a sealed foil pouch inargon and (2) sterilized and aged in a gas permeable Tyvek® pouch, thusexposed to air. The Tyvek® pouch allows permeation of air, whilepreserving sterility. The expanded time scale compared to FIG. 2illustrates the dramatic unexpected difference in the decay of freeradicals in an inert atmosphere compared to an oxygen-containingenvironment.

The above stabilization methods may be accomplished in a number of ways.In an exemplary embodiment, in a first step, prior to sterilization, thestent is placed in a gas permeable pouch such as a Tyvek® pouch. FIG. 5Adepicts a schematic representation of a Tyvek® pouch 120 with a stent122 contained within. The pouch will allow oxygen to pass through toterminate any free radicals generated during sterilization to preventany post-sterilization molecular weight change associated with freeradicals, while preserving the sterility level of the stent. Materialsother than Tyvek® that are gas permeable and that also preserve asterility level may be used in this embodiment and others describedherein. Although the pouch is permeable to air, it will block thepermeation of bioburden to maintain the sterility levelpost-sterilization. The stent may be kept in the pouch a period of timeuntil the molecular weight of the scaffolding polymer of the stent isstabilized by the oxygen exposure. In a second step, the gas permeablepouch can be disposed within a gas impermeable pouch, such as analuminum pouch. FIG. 5B depicts Tyvek® pouch 120 disposed withinaluminum pouch 124. The gas impermeable pouch may then be evacuated,backfilled with an inert gas, and sealed for long term storage or untilimplantation.

Other embodiments of the present invention include exposing thescaffolding to radiation in an inert gas environment. Followingradiation exposure in the inert gas environment, the scaffolding isexposed to an oxygen-containing gas. The exposure the oxygen-containinggas can continue for a period of time after the radiation exposure. Theperiod of time may be sufficient to prevent any further molecular weightchange. The stent may then be stored in an inert gas atmosphereindefinitely, for example, until implantation. An exemplary molecularweight profile according to these embodiments is illustrated by study Ein Table 1 and FIG. 9.

The inventors have observed that exposure of polymer scaffolding to airduring sterilization results in a greater drop in Mn than sterilizationin an inert gas environment (see FIG. 9). E-beam radiation in a gas withhigh oxygen content may generate ozone which is highly reactive and canreact with polymer chains of the stent or with a drug in the stent.

These other embodiments involving exposure to oxygen-containing gasafter radiation exposure may be accomplished in a variety of ways. In anexemplary embodiment, a method involves packaging a stent in adouble-layered pouch. The first or inner layer is gas permeable, such asa Tyvek® pouch, and the second or outer layer is gas impermeable, suchas an aluminum pouch. FIG. 6 depicts a schematic representation of adouble-layered pouch 130. Pouch 130 has an inner gas permeable Tyvek®layer 132 and an outer gas impermeable aluminum layer 134. Stent 136 isdisposed within the inner Tyvek® layer. Prior to and during E-beamsterilization the outer layer is sealed and contains an inert gasenvironment ant the stent is sealed within the Tyvek® layer, also in aninert gas environment. Post-sterilization, the aluminum layer is opened,or more generally, fluid communication is allowed between the outerpouch and ambient air to allow air into the pouches, which exposes thestent to air. Outer pouch 134 has a sealable opening 138 that can beopen and closed to allow exposure to air and sealed from exposure toair, respectively. For example, sealable opening 138 has a foil seal138A and a Tyvek® window 139B that allows air to enter pouch 134. Thestent is exposed to the air for at least a period of time to stabilizethe molecular weight of the stent scaffolding polymer. The foil pouchmay then be backfilled with inert gas and resealed. Alternatively, anadditional foil pouch may be added outside of the double layer pouch,evacuated, backfilled with inert gas, and resealed.

The inventors have found that the cumulative free radicals terminateddepend on the time of exposure to the oxygen-containing gas. Thus, theoxygen exposure may continue until the concentration of free radicalslevels decays below a selected value. For example, the selectedconcentration can be 5×10⁷ DI/mg.

Following the exposure to oxygen for the period of time, the scaffoldingmay then be disposed into an inert gas environment or the gas may beremoved from the packaged backfilled with an inert gas.

The oxygen-containing gas can have any concentration of oxygen thatstabilizes (e.g., within 10%) the molecular weight (Mn) as observed overa period of at least 2 weeks, 1 month, or 2 months. Alternatively oradditionally, the oxygen-containing can have any concentration of oxygenthat causes the free radical concentration to decay to below a certainlevel (e.g., 5×10⁷ DI/mg) in less than 1 hr, 5 hrs, 12 hrs, 1 day, 2days, or less than 5 days.

For example, air may be used which is 20.95 mol % oxygen. The balance ofthe gas can include an inert gas(s) and possible other residual gasimpurities. The concentration of oxygen in the gas can be less than 1%,1 to 5%, 5-10%, more than 10% to air concentration, air concentration to40 mol %, 40 to 60%, 60 to 90%, 90-95%, or greater than 95%.

The inventors also found that the rate of free radical decay depends onthe concentration of oxygen. The lower the concentration of oxygen, thelonger the time required to reach a given concentration of freeradicals. Exemplary exposure times may be less than 10 min, 10 min to 1hr, 1 to 3 hr, 3 to 6 hr, 6 to 9 hr, 9 to 12 hr, 12 hr to 1 day, 1 to 2days, 2 to 3 days, 3 to 5 days, or greater than 5 days.

In further embodiments, the stent may be packaged and stored untilrelease and implantation in an atmosphere that is a mixture of inert gasand oxygen. The mixture is primarily an inert gas with a very low oxygencontent that is substantially lower than that of air, but greater thanthe residual content of an evacuated and inert gas backfilled package.The packaged stent may then be radiation sterilized and stored in theatmosphere indefinitely, for example, until release and implantation.“Release” refers to release or shipping from a manufacturer orcontractor of the manufacturer in a ready-to-implant condition. Thestorage time from sterilization may be 1 to 10 days, 10 days to 1 month,1 to 3 months, 3 to 6 months, 6 months to 1 year, 1 to 2 years. Theconcentration of oxygen in the gas mixture may be high enough to causethe free radical concentration to decay to below a certain level (e.g.,5×10⁷ DI/mg) in less than 5 hrs, 12 hrs, 1 day, 2 days, or less than 5days. The concentration of oxygen should be low enough that storage forany of the storage ranges disclosed will not result in adverse effectson the molecular weight of the polymer of the stent or drug. Inexemplary embodiments, the content of oxygen may be less than 0.5%, 0.5to 1%, 1 to 2%, 0.08 to 1.02%, 2 to 3%, 3 to 5%, 5 to 10%, less than 1%,less than 5%, less than 10%, or 10 to 20%.

In some embodiments, prior to sterilization, the scaffold is placed in agas impermeable package and the atmosphere in the package, i.e., air,may be evacuated and then the package may be backfilled with the inertgas-oxygen mixture. For example, the same equipment may be used as thatfor evacuating and backfilling the package with inert gas, whichbackfills the package from an argon cylinder. In the present invention,the package may be backfilled with the inert gas/oxygen mixture with thecontrolled amount of oxygen. The molecular weight profile according tothese embodiments is illustrated by study C in Table 1 and FIG. 9.

Studies have shown for a gas mixture with an oxygen content of 1% thatno free radicals can be detected after 2 days, whereas a signal is stilldetected at 28 days using an inert gas atmosphere. FIG. 7 depicts thefree radical decay in irradiated PLLA scaffolding samples sterilized andstored in containers with different oxygen concentrations, 0%, 0.002%,and 1%. The free radical decay of samples in 0.002% oxygen is more rapidthan the 0% oxygen, but the long term decay is similar. The free radicaldecay of the samples in 1% oxygen samples is significantly faster thanin the 0% or 0.002% oxygen.

Table 1 is a summary of the studies on the effect of E-beamsterilization on PLLA scaffolding samples. The samples in study A werenot sterilized to provide a basis for comparison of the effect of E-beamradiation on molecular weight. The samples in studies B-E weresterilized with E-beam radiation with a dose of 27.5 kGy. Thesterilization and storage conditions are in Table 1 for each study. FIG.8 depicts the Mn versus time of a PLLA scaffolding corresponding tostudy A. The Mn is fairly constant as expected.

TABLE 1 Summary of studies on the effect of E-beam radiation on PLLAscaffolding samples. Sterilization conditions Storage conditions Studyfor samples for samples A Non-sterile - no irradiation RT¹ storage insealed foil pouch in argon B Sterilize in foil pouch in RT storage insealed foil argon pouch in argon C Sterilize in foil pouch in 1% RTstorage in sealed foil O₂ pouch in argon D Sterilize in Tyvek ® RTstorage in sealed Tyvek ® pouch - exposed to air pouch in argon ESterilize in foil pouch in 1. Expose to samples to air for argon 24 hrs2. Seal and repack units in foil pouch in argon ¹RT = Room TemperatureData collection A-D: 0, 1, 3, 7, 14, 21, 28, 35, 56, (180) days Datacollection E: 3, 7, 14, 21, 28, 35, 56, (180) days

FIG. 9 depicts the Mn versus time for the samples of studies B-E. Forstudy B, the sterilization and storage in inert gas and the effect werediscussed above. In study B, the scaffolding Mn increased from about 80kDa post-sterilization to above 100 kDa after about 60 days.

The comparison between study A, FIG. 8, and study B, FIG. 9, reveals thedramatic effect that radiation has on the long term behavior of Mn. Theprofile of Mn for study C, which is sterilization and storage in a 1%oxygen gas, in FIG. 9 shows only a slight increase in Mn the first dayor so with stable Mn after the increase. For study D, which issterilization in air, the initial Mn is lower than for studies B and Cand is stable throughout the range studied. For study E, the initialmolecular weight is also lower than for studies B and C and is stablethroughout the range studied. The molecular weight for study D isslightly higher than for study E. This presence of oxygen during thesterilization in study D may increase the radiation induced chainscission resulting in a lower Mn.

A preferred embodiment used in the above studies has the stent patterndescribed in U.S. application Ser. No. 12/447,758 (US 2010/0004735) toYang & Jow, et al. Other examples of stent patterns suitable for PLLAare found in US 2008/0275537. The cross-section of the struts of thescaffold is 150×150 microns.

Above it was stated that the molecular weight and properties of apolymeric stent can be stabilized after sterilization by aging a stentat room temperature or a slightly higher temperature. However, the finalmolecular weight after stabilizing would be a high end value at the endof the stabilization period. The methods of the present inventiondiscussed above involve quenching the free radicals during or aftersterilization so that the molecular weight is stabilized at or close tothe molecular weight at the end of radiation sterilization.

Further embodiments of the present invention include allowing themolecular weight to increase for a period of time after sterilization,followed by stopping the molecular weight change through exposure of thestent to oxygen to stabilize the polymer at a desired Mn. The stabilizedMn can be any value between the Mn immediately after sterilization tothe high end value at the end of stabilization through room temperaturestabilization discussed above.

The method can include radiation sterilizing a stent disposed in apackage with an inert gas atmosphere. After a selected period of time,the stent can then be exposed to an oxygen-containing gas, preferably, ahigh content of oxygen content such as air. The oxygen content may behigh enough to rapidly terminate or quench the free radicals to stop theincrease in molecular weight at a desire valued of Mn. For example, thefree radical concentration may decay to less than 5×10⁻⁷ DI/mg in lessthan 2 days, 1 day, 12 hr, 5 hr, 1 hr. The oxygen content of the gas maybe greater than 5%, 5 to 10%, greater than 10%, 10 to 20%, 20% to airconcentration, or greater than air concentration.

The method can include selecting a desired final Mn of the polymerscaffolding of the stent. The Mn versus time relationshippost-sterilization may be determined in an inert gas atmosphere, such asthat shown in FIG. 3. The selected time required for the scaffoldingpolymer to reach selected Mn may be obtained from the relationship. Ascaffolding with the selected Mn may then be obtained by exposing ascaffolding packaged in an inert atmosphere at the selected timepost-radiation sterilization.

The above method may be achieved in a variety of ways. In oneembodiment, a radiation sterilized stent may be placed in a pouch withtwo sides or enclosures. One side is made of a gas impermeable materialsuch as aluminum and the other side is made of gas permeable material,Tyvek®. FIG. 10 depicts a schematic representation of a two-sided pouch140 having a gas impermeable aluminum side 142 and a gas permeableTyvek® side 144, which has air within. The two sides are sealed from oneanother and are connected by a movable sealer 146 that allows movementof a stent 148 from the aluminum side to the Tyvek® side without fluidcommunication between the sides. Before sterilization, stent 148 isplaced in the aluminum side in an inert gas. The stent is sterilized andafter a certain time post-sterilization, the sealer shifts the stent(shown in phantom) to the Tyvek® side, as shown by arrow 150, toterminate free radicals, and therefore to stop Mn change. After aselected stabilization time, the stent is shifted back to the aluminumside to the inert gas environment. The stent may then be stored in aninert gas environment by refilling with inert gas and resealing.

Alternatively, a package can have three compartments, a firstcompartment, a second compartment, and a third compartment. The secondcompartment that contains the stent is separated from the firstcompartment and the third compartment by a zipper or resealable tape.The zipper or tab can be positioned to allow or close off fluidcommunication between the first or third compartments. The firstcompartment and the second compartment are gas impermeable, for example,made of aluminum, and filled with inert gas. The third compartment isgas permeable, e.g., made of Tyvek®, and filled with air. Duringsterilization, the stent would remain in the second compartment and issealed off from both the first and third compartments. Aftersterilization, the zipper or tab between the second and the thirdcompartment is opened, exposing stent to air. After a certain time, thesame zipper or tab is closed, and then the zipper or tab between thefirst and the second compartment is opened, exposing the stent to theinert gas environment again.

In another embodiment, both sides of a pouch may be made from gasimpermeable material such as aluminum. FIG. 11 depicts a schematicrepresentation of a pouch 160 with two gas impermeable sides, a firstaluminum side 162 and a second aluminum side 164. Prior to and duringsterilization the first side 162 is filled with inert gas, while thesecond side 164 is filled with a mixture of an inert gas and oxygen.Prior to and during sterilization, a stent 166 is disposed in the firstside 162 and the two sides are not fluidly connected. A selected periodof time after sterilization when the Mn of the scaffolding reaches aselected Mn, the mixture of inert gas and oxygen may be used toterminate free radical recombination. For example, the mixture may haveat least 1% oxygen, 1-5% oxygen, 5-15% oxygen, 15-20% oxygen, or is air.The two sides may be connected by a valve 168 that allows the two sidesto be fluidly connected when the valve is open and sealed from oneanother when the valve is closed. During sterilization and a selectedperiod time after sterilization valve 168 may be closed. After theselected period of time, valve 168 may be opened to allow the exposureof the stent to the inert gas and oxygen mixture to terminate the freeradicals and stabilize the molecular weight at the selected Mn. Afterthe molecular weight is stabilized valve 168 may be closed and the gasin the first side 162 may be replaced with an inert gas atmosphere.

For the purposes of the present invention, the following terms anddefinitions apply:

The “Tyvek®” packaging herein refers to Tyvek® medical packaging fromDupont of Wilmington, Del. such as DuPont™ Tyvek® 1073B.

The term “molecular weight” can refer to one or more definitions ofmolecular weight. “Molecular weight” can refer to the molecular weightof individual segments, blocks, or polymer chains. “Molecular weight”can also refer to weight average molecular weight or number averagemolecular weight of types of segments, blocks, or polymer chains. Thenumber average molecular weight (Mn) is the common, mean, average of themolecular weights of the individual segments, blocks, or polymer chains.Molecular weight is typical expressed in grams/mole which is referred toas “Daltons.” It is determined by measuring the molecular weight of Npolymer molecules, summing the weights, and dividing by N:

${\overset{\_}{M}}_{n} = \frac{\sum\limits_{i}{N_{i}M_{i}}}{\sum\limits_{i}N_{i}}$

where Ni is the number of polymer molecules with molecular weight Mi.The weight average molecular weight is given by

${\overset{\_}{M}}_{w} = \frac{\sum\limits_{i}{N_{i}M_{i}^{2}}}{\sum\limits_{i}{N_{i}M_{i}}}$

where Ni is the number of molecules of molecular weight Mi Unlessotherwise specified, “molecular weight” will refer to number averagemolecular weight (Mn).

“Semi-crystalline polymer” refers to a polymer that has or can haveregions of crystalline molecular structure and amorphous regions. Thecrystalline regions may be referred to as crystallites or spheruliteswhich can be dispersed or embedded within amorphous regions.

The “glass transition temperature,” Tg, is the temperature at which theamorphous domains of a polymer change from a brittle vitreous state to asolid deformable or ductile state at atmospheric pressure. In otherwords, the Tg corresponds to the temperature where the onset ofsegmental motion in the chains of the polymer occurs. When an amorphousor semi-crystalline polymer is exposed to an increasing temperature, thecoefficient of expansion and the heat capacity of the polymer bothincrease as the temperature is raised, indicating increased molecularmotion. As the temperature is increased, the heat capacity increases.The increasing heat capacity corresponds to an increase in heatdissipation through movement. Tg of a given polymer can be dependent onthe heating rate and can be influenced by the thermal history of thepolymer as well as its degree of crystallinity. Furthermore, thechemical structure of the polymer heavily influences the glasstransition by affecting mobility.

The Tg can be determined as the approximate midpoint of a temperaturerange over which the glass transition takes place. [ASTM D883-90]. Themost frequently used definition of Tg uses the energy release on heatingin differential scanning calorimetry (DSC). As used herein, the Tgrefers to a glass transition temperature as measured by differentialscanning calorimetry (DSC) at a 20° C./min heating rate.

“Stress” refers to force per unit area, as in the force acting through asmall area within a plane. Stress can be divided into components, normaland parallel to the plane, called normal stress and shear stress,respectively. Tensile stress, for example, is a normal component ofstress applied that leads to expansion (increase in length). Inaddition, compressive stress is a normal component of stress applied tomaterials resulting in their compaction (decrease in length). Stress mayresult in deformation of a material, which refers to a change in length.“Expansion” or “compression” may be defined as the increase or decreasein length of a sample of material when the sample is subjected tostress.

“Strain” refers to the amount of expansion or compression that occurs ina material at a given stress or load. Strain may be expressed as afraction or percentage of the original length, i.e., the change inlength divided by the original length. Strain, therefore, is positivefor expansion and negative for compression.

“Strength” refers to the maximum stress along an axis which a materialwill withstand prior to fracture. The ultimate strength is calculatedfrom the maximum load applied during the test divided by the originalcross-sectional area.

“Modulus” may be defined as the ratio of a component of stress or forceper unit area applied to a material divided by the strain along an axisof applied force that results from the applied force. The modulustypically is the initial slope of a stress-strain curve at low strain inthe linear region. For example, a material has both a tensile and acompressive modulus.

The tensile stress on a material may be increased until it reaches a“tensile strength” which refers to the maximum tensile stress which amaterial will withstand prior to fracture. The ultimate tensile strengthis calculated from the maximum load applied during a test divided by theoriginal cross-sectional area. Similarly, “compressive strength” is thecapacity of a material to withstand axially directed pushing forces.When the limit of compressive strength is reached, a material iscrushed.

“Toughness” is the amount of energy absorbed prior to fracture, orequivalently, the amount of work required to fracture a material. Onemeasure of toughness is the area under a stress-strain curve from zerostrain to the strain at fracture. The units of toughness in this caseare in energy per unit volume of material. See, e.g., L. H. Van Vlack,“Elements of Materials Science and Engineering,” pp. 270-271,Addison-Wesley (Reading, Pa., 1989).

The underlying structure or substrate of an implantable medical device,such as a stent can be completely or at least in part made from abiodegradable polymer or combination of biodegradable polymers, abiostable polymer or combination of biostable polymers, or a combinationof biodegradable and biostable polymers. Additionally, a polymer-basedcoating for a surface of a device can be a biodegradable polymer orcombination of biodegradable polymers, a biostable polymer orcombination of biostable polymers, or a combination of biodegradable andbiostable polymers.

It is understood that after the process of degradation, erosion,absorption, and/or resorption has been completed, no part of the stentwill remain or in the case of coating applications on a biostablescaffolding, no polymer will remain on the device. In some embodiments,very negligible traces or residue may be left behind. For stents madefrom a biodegradable polymer, the stent is intended to remain in thebody for a duration of time until its intended function of, for example,maintaining vascular patency and/or drug delivery is accomplished.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. (canceled)
 2. A method of making a stent, comprising: providing apolymeric stent scaffolding disposed on a catheter; exposing thescaffolding to E-beam radiation for sterilization, wherein thescaffolding is exposed to a gas containing oxygen during the exposure,wherein the exposure to the gas containing oxygen is performed at leastuntil a free radical concentration of the gas is less than 5×10⁷ DI/mgand/or at least until the number average molecular weight (Mn) of thescaffolding is stabilized, wherein an oxygen content of the gas is 1% orgreater; and followed by packaging the scaffolding in an inert gasenvironment.
 3. The method of claim 2, wherein the oxygen-containing gasis air.
 4. The method of claim 2, an oxygen content of the gas is 1 to10%.
 5. The method of claim 2, wherein the inert gas environment has anoxygen content of less than 0.002%.
 6. The method of claim 2, whereinthe polymeric stent scaffolding is exposed 8 to 24 hr to theoxygen-containing gas after the E-beam exposure.
 7. The method of claim2, wherein during sterilization, the scaffolding is within a packagethat allows permeation of air into the package.
 8. The method of claim2, wherein a dose of the radiation exposure is between 20-50 kGy.
 9. Themethod of claim 2, wherein stabilizing comprises less than a 10% changein Mn over a selected time period.
 10. The method of claim 9, whereinthe selected time period is at least 30 days, 30 to 60 days, or greaterthan 60 days.
 11. The method of claim 2, wherein: prior to E-beamexposure: the scaffolding is sealed in a package permeable to andcomprising air, wherein oxygen in the air quenches free radicalsgenerated by the radiation exposure, and after the radiation exposure:the package is disposed in a gas impermeable package, the air is removedfrom the packages, and the packages are filled with an inert gas andsealed.
 12. A method of making a stent, comprising: providing apolymeric stent scaffolding; exposing the scaffolding to E-beamradiation for sterilization, wherein the scaffolding is exposed to aninert gas environment during sterilization; exposing the irradiatedscaffolding to air to quench free radicals generated by the radiationexposure and stabilize a molecular weight of the scaffolding polymer,wherein the exposure to the air is performed at least until the freeradical concentration is less than 5×10⁷ DI/mg and/or the stabilizedscaffolding polymer has less than a 10% change in Mn over a selectedtime period; and after stabilizing, packaging the scaffolding in aninert gas environment.
 13. The method of claim 12, wherein the radiationexposure is between 20-50 kGy.
 14. The method of claim 12, wherein theselected time period is at least 30 days, 30 to 60 days, or greater than60 days.
 15. A method of making a stent, comprising: packaging apolymeric stent scaffolding in a sealed gas impermeable package forstorage until use, wherein the package contains a mixture of inert gasand oxygen and a content of the oxygen in the gas mixture is 0.5% to 2%;and exposing the packaged scaffolding to E-beam radiation forsterilization, wherein the oxygen in the gas mixture quenches freeradicals in the scaffolding polymer generated during radiation exposureand stabilizes the molecular weight of the scaffolding polymer such thata number average molecular weight (Mn) of the stabilized scaffoldingpolymer changes less than 10% during storage.
 16. The method of claim15, wherein the free radical concentration is less than 5×10⁷ DI/mg inless than 2 days after exposure.
 17. A method of making a stent,comprising: disposing a polymeric stent scaffolding in a gas-impermeablepackage; vacuum evacuating the package followed by backfilling of thepackage with an inert gas; repeating the evacuation and backfill processto further reduce oxygen content in the package; exposing the package toE-beam radiation for sterilization of the scaffolding, wherein an oxygencontent in the package during the exposing is 0.5 to 3%; and releasingthe sterilized package for storage and/or shipping.
 18. The method ofclaim 17, wherein a required dose of the radiation for sterilization is20-50 kGy.
 19. The method of claim 17, wherein the package is exposed toa required dose for sterilization in multiple passes of E-beam exposure.20. The method of claim 17, wherein the scaffolding comprises PLLA.